neue aspekte in diagnostik und therapie der hyperprolaktinämie prof. dr. l. wildt klinik für...
TRANSCRIPT
Neue Aspekte in Diagnostik und Therapie der Hyperprolaktinämie
Prof. Dr. L. Wildt
Klinik für Gynäkologische Endokrinologie und Reproduktionsmedizin
Medizinische Universität Innsbruck
Hormonell - Aktuell Zypern 2008
Diagnosis, Symptoms and Aetiology of
Hyperprolactinaemia
Prolaktin/Laktotropin
Struktur• 199 AS - MG 23kD
Verwandtschaft• GH & hpL
Bildungsorte• Hypophysenvorderlappen• Endometrium• Dezidua (in der SS)• Lymphozyten
What is prolactin?• Monomeric peptide
hormone1 – 23 kDa (199 residues)– Closely related to
growth hormone and placental lactogen
• Secreted from lactotrophs in the anterior pituitary2
• Produced by Endometrium,
Decidua...
• Main role to promote milk secretion2
1From Li CH. In Greep RO (ed): Handbook of Physiology IV, part 2. Baltimore, Williams & Wilkins, 1974.
2Freeman et al. Physiol Rev 2000; 80(4): 1523–1631.
0
100
200
300
400
500
600
1 2 3 4 5 6 7 8 9 10 11 12
Fraction
Pro
lac
tin
(m
UI/
L)
23 kD
50 kD
170 kD
Monomeric prolactin demonstrated by column chromatography
HypothalamusNo dopamine
released
Pituitary lactotroph
HypothalamusDopamine released
Pituitary lactotroph
Prolactin released Prolactin inhibited
Prolactin released into bloodTargets mammary glands to
produce milk
GnRH TRH+ +
+
Prolactin release inhibited
+
Dopamine inhibits
the release of prolactin
D2 receptor
Role of Dopamine
Measurement of prolactin levels
• Avoid circadian increase
• Rule out use of drugs
• Minimise stress
• Avoid nipple stimulation
Prolactin at 0 minutes (μg/L)
Pro
lac
tin
at
30 m
inu
tes
(μg
/L) Time at which sample was taken (hours)
Pro
lac
tin
(μ
g/L
)
What is hyperprolactinaemia?
• Hyperprolactinaemia is an abnormally high level of prolactin in the blood:– Mild–moderate 26–100 μg/L– Severe >100 μg/L (Suspicious for
Prolaktinoma)
• Normal levels of prolactin in the blood:– 10–25 µg/L (women when not pregnant or
lactating)– 5–10 µg/L (men)
Rule out macroprolactinaemia• Prolactin molecules
can aggregate on non-specific antibodies (Defined as Macroprolactin)
• Macroprolactin is an inactive form of prolactin
• Column chromatography or polyethylene glycol precipitation can identify macroprolactin
• 30 % of cases. Does not require treatment
Column chromatography of prolactin molecules in four women
Fraction
Fraction
Fraction
Fraction
Pro
lac
tin
(μ
g/L
)
Pro
lac
tin
(μ
g/L
)
Pro
lac
tin
(μ
g/L
)
Pro
lac
tin
(μ
g/L
)
Monomeric
Rodriguez Espinosa et al. Gestion del laboratorio clínico MAPFRE Ed. Madrid 2000.
Macro-prolactinaemia
Monomericand
macro
Macroand
monomeric
Hyperprolactinaemia is common in women with reproductive disorders
Molitch ME and Reichlin S. Adv Intern Med 1980; 26: 37–65.
25.8%
74.2%
Galactorrhoea only
Normal prolactin levels
Hyperprolactinaemia
Amenorrhoea plus galactorrhoea
22.5%
77.5%
87.2%
12.8%
Amenorrhoea only
Effect of prolactin levels on menstruation
0
20
40
60
80
100
120
140
Normal cycle Irregular cycles Amenorrhoea
Pro
lact
in (
ng
/mL
)
*
*Upper limit has not been determined and may exceed 140 ng/mL prolactin
Aetiology of hyperprolactinaemia• Physiological1
– Pregnancy– Lactation– Stress, sleep,
exercise• Pituitary disorders
– Pituitary tumours2
– Acromegaly3
• Hypothalamic disorders – Primary
hypothyroidism3
• Medication4, 5 – Anti-psychotics– Anti-emetics– Anti-hypertensives
• Other – Macroprolactinaemia6 – Chest wall injuries7
– Renal or liver failure7
1Freeman et al. Physiol Rev 2000; 80(4): 1523–1631; 2Mah and Webster. Semin Reprod Med 2002; 20(4): 365–374; 3Asa and Ezzat. Nat Rev Cancer 2002; 2(11): 836–849; 4Marken et al. Clin Pharm 1992; 11(10): 851–856; 5Verhelst and Abs. Treat Endocrinol 2003; 2(1): 23–32; 6Yuen et al. Hong Kong Med J 2003; 9(2): 119–121; 7Serri et al. CMAJ 2003; 169(6): 575–581.
Prolactinomas
• Prolactinomas1,2
– Most frequent cause of persistent hyperprolactinaemia (~50%)
– Primarily benign
– Account for 25–30% of functional pituitary tumours
– <10 mm microprolactinomas
– ≥10 mm macroprolactinomas
1Mah and Webster. Semin Reprod Med 2002; 20(4): 365–374. 2Asa and Ezzat. Nat Rev Cancer 2002; 2(11): 836–849. Figure: http://www.mja.com.au/public/issues/180_08_190404/hur10511_fm-3.gif
OC=optic chiasm; arrow pointsto prolactinoma
Prolactinoma in the pituitary
Symptoms associated with hyperprolactinaemia
• Reproductive function symptoms1
– Premenopausal women • Hypogonadism (infertility,
irregular menstruation, oligomenorrhoea, amenorrhoea)
• Decreased libido
– Postmenopausal women • Disappearance/absence of
hot flushes
– Men2
• Decreased libido• Impotence• Infertility
• General symptoms– Galactorrhoea1
– Osteoporosis3
– Significant weight gain (up to 22 kg)
• Pressure symptoms– Headaches
– Visual field defects
– External ophthalmoplegia
– Hydrocephalus (rare)
1 Luciano. J Reprod Med 1999; 444(12 Suppl): 1085–1090.
2 Serri et al. CMAJ 2003; 169(6): 575–581.3 Vartej et al. Gynecol Endocrinol 2001; 15(1): 43–47.
HyperprolactinemicHypothalamic
Differential Diagnosis of Anovulation
FSH LH
LH/FSH-Ratio
Prolactin
TestosteroneSHBG/FAI
DHEAS
elevated elevatedelevated
Primary
normal
Hyperandrogenemic
PRL-Bestimmung
>100 ng/ml
andere Ursachen ausgeschlossen
(Med., Schwangersch. u.a.)
Wert bei Kontrollebestätigt
Weitere Diagnostik und Festlegungder Therapie durch Spezialisten
Klinischer Verdacht auf ein Prolaktinom
normal
Prolaktinomausgeschlossen
MRT der Hypophyse
erhöht, aber <100 ng/ml
Diagnosis• Measurement of serum prolactin levels
– Normal levels in women=10–25 ng/ml– Hyperprolactinaemia
• Mild–moderate 26–100 ng/ml• Severe >100 ng/ml (Suspicious for Prolaktinoma)
• Rule out macroprolactinaemia• Rule out hyperandrogenemia/PCO
(frequently associated with Prolactin levels 26-60 ng/ml)
Medical history/clinical examination• Blood biochemistry (including pregnancy and renal
and thyroid function tests TSH) • Magnetic resonance imaging (MRI) of pituitary and
hypothalamic region
Importance & prevalence of hyperprolactinaemia
Etiology of Anovulation in Infertile patients N= 1000
Hyperandro-
genemia
Hypothalamic
Hyperprolactinemia
Primary
45 %
34 %
12 %
9 %
Hyperprolactinaemia is a common endocrine disorder
• The prevalence of hyperprolactinaemia is difficult to establish:– Not all sufferers are symptomatic or undergo
diagnosis
• Estimates of prevalence1 in different populations:– Unselected normal population: ~0.4% – Family planning clinic population: 5% – Women with reproductive disorders: up to 17%
1Biller et al. J Reprod Med 1999; 44:1075–1084.
Therapy of Hyperprolactinemia Pharmacotherapy:Dopamine Agonists
Bromocriptine Quinagolide Cabergoline
First-line therapies for the treatment of hyperprolactinaemia
Non-ergot derived selective D2-type DA
receptor agonist
Ergot derived, non-specific DA receptor agonist/antagonist
Ergot derived selective D2-type
DA receptor agonist
Oldest; least well tolerated
2nd generation; better tolerated and more effective than bromocriptine
Lisuride
Ergot derived, non-specific DA receptor
activity
Better tolerated than Bromocriptine
Licensed Indications
• NORPROLAC Hyperprolactinaemia (idiopathic or due to prolactinoma)
• Dostinex Hyperprolactinaemia (idiopathic or due to prolactinoma), related disorders
• Parlodel Hyperprolactinaemia, acromegaly
Parkinson’s disease• Dopergin: Hyperprolactinemia,
Parkinsons`disease
Pharmacotherapy – potential complications
• Treatment intolerance
• Treatment resistance
• Recurrence following treatment withdrawal
• Pregnancy
• Compliance
• Severe Side effects
Side effects of antidopaminergic drugs for
treatment of Hyperprolactinemia • Minor side effects(Frequency similar, but severity different for all dopaminergic drugs)
NauseaVomitingConstipationLow blood pressureFatigueInsomnia
Minor side effects are dose dependent,
Resistance to treatment
• Defined as no normalization of Prolactin levels within 6-8 Weeks (functional hyperprolactinemia or Adenoma)
• Occurs in 10 – 20 % of patients.
• Our own data in 850 Patients treated since 1980 show: 15 % primary resistance to Bromocriptine (n=400)
10 % primary resistance to cabergoline (n= 150)
15 % primary resistance to lisuride (Dopergin) (n=100)
5 % primary resistance to quinagolide (n= 200)
up to 5 % of patients are resistant to all dopamine-agonistsMattle und Wildt, in prep.
Recurrence rate after discontinuation of Cabergoline therapy
Colao et al 2003
200 Patients
Inclusion criteria: normalized Prolactin, no tumor or Tumorreduction > 50%, Distance Chiasma opt. > 5 mm, no invasion
Recurrence within 2 – 5 years after discontinuation
Functional Hyperprolactinemia: 24 %
Microprolactinoma: 31 %
Macroprolactinoma: 36 %
Treatment during pregnancy I • Bromocriptine:
– Not associated with detrimental effects on pregnancy or foetal development1
– Treatment suspension recommended upon confirmation of pregnancy• Quinagolide:
– Indicated for use until pregnancy confirmed– No tetarogenic effects during early pregnancy reported (limited data)2, 3
• Cabergoline: – Not approved for use during pregnancy (limited data)– Recommended to cease treatment ≥1 month prior to conception– Repeated pregnancy tests are recommended– Not associated with detrimental effects4
1Weil. Curr Med Res Opin 1986; 10(3): 172–195; 2Disarno et al. J Clin Endocrinol & Metab 2001; 86(11): 5256–5261; 3Schultz et al. Pituitary 2000; 3(4): 239–249; 4Robert et al. Reprod Toxicol 1996; 10(4): 333–367.
Treatment during pregnancy II • When pregnancy is confirmed treatment should be discontinued in cases
of functional hyperprolactinemia. However, treatment during early pregnancy may reduce abortion rate
• In case of pituitary adenomas, treatment can be either continued or discontinued. The choice has to be an individualized decision made by the physician and the informed patients.
• In case of macroprolactinomas, we recommend visual field examination each trimester and MRT once or twice.
• We encourage lactation and breastfeeding, even in the case of makroprolaktinomas under controlled conditions (i.e regular visual field examination and MRT)
Side effects of antidopaminergic drugs for
treatment of Hyperprolactinemia • Minor side effects(Frequency similar, but severity different for all dopaminergic drugs)
NauseaVomitingConstipationLow blood pressureFatigueInsomnia
• Major side effects(only with ergot-derivatives, not observed for quinagolide)
Pulmonary FibrosisElevated LiverenzymesMania, psychiatric symtomsVasoconstrictionRaynauds Disease (Vaskular constriction may be observed in ~20% of patients)ThrombocytosisInterstitial pneumonitisgastrointestinal bleeding„Leaky heart“ syndrome
Minor side effects are dose dependent, major side effects appear to be independent on dose
Risk for valvulopathy
moderate or severe grades
Pergolide 23%
Cabergoline 29%
Control 6%
Alternate therapies: Surgery
(Pituitary Adenomas)Pulsatile GnRH
Naltrexone
Surgery1
• For pharmacotherapy-resistant prolactinomas
• Consideration should be made for surgery-associated complications including1:– Pituitary deficiency– Visual disturbance– Mortality
• Recurrence can occur following surgery (30-60 %)
1Serri et al. CMAJ 2003; 169(6): 575–581.
Transsphenoidal Resection of Prolactinoma
• Microadenoma
72 %
17 %
60 %
.27%
.4 %
• Macroadenoma
30 %
20 %
25 %
0.9 %
6.9%
Instant Normalization of Prolactin
Recurrence
Long term normalization
Mortality
Morbidity
Radiotherapy1
• Considered if pharmacotherapy and surgery fail• Conventional radiotherapy can induce
hypopituitarism• In comparison, gamma-knife (GKS) and focal
radiation surgeries:– Deliver higher radiation doses– Reduce radiation exposure outside the target area– Are more effective in a single session
1Tsang et al. Radiother Oncol 1996; 41(1): 45–53.
Summary
• Hyperprolactinemia is a frequent cause of ovarian insufficiency and infertility• It is caused in ~ 50 % by tumors, 50 % are functional.• Treatment is primarily medical • For medical treatment, mainly Bromocriptine, Cabergoline, Lisuride and
Quinagolide are used. • Bromocriptine therapy has been widely abandonned, mainly because of side
effects. • Cabergoline therapy is effective in normalization of Prolactin –levels, but
compliance may give problems when used for long-time treatment. It has to be discontinued 4 weeks befor pregancy is attempted. It may have severe side effects
• The advantages of treatment with quinagolide consist in the excellent effectiveness and good tolerabilty, the daily dosage regime, its licensed use until the dignosis of pregnancy and the lack of ergot-related side effects.
Prolaktinom Therapie
Medikamente
Operation
Bestrahlung